β–sarcoglycan, a 43 kDa dystrophin–associated glycoprotein, is an integral component of the dystrophin–glycoprotein complex. We have cloned human β–sarcoglycan cDNA and mapped the β–sarcoglycan gene to chromosome 4q12. Pericentromeric markers and an intragenic polymorphic CA repeat cosegregated perfectly with autosomal recessive limb–girdle muscular dystrophy in several Amish families. A Thr–to–Arg missense mutation was identified within the β–sarcoglycan gene that leads to a dramatically reduced expression of β–sarcoglycan in the sarcolemma and a concomitant loss of adhalin and 35 DAG, which may represent a disruption of a functional subcomplex within the dystrophin–glycoprotein complex. Thus, the β–sarcoglycan gene is the fifth locus identified (LGMD2E) that is involved in autosomal recessive limb–girdle muscular dystrophy.
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